This invention relates to certain substituted thiazolidinedione derivatives, to a process for preparing such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds and compositions in medicine.
European Patent Applications, Publication Numbers 0008203, 0139421, 0155845, 0177353, 0193256, 0207581 and 0208420 relate to thiazolidinedione derivatives which are disclosed as having hypoglycaemic and hypolipidaemic activity. Chem. Pharm. Bull 30 (10) 3580-3600 also relates to certain thiazolidinedione derivatives having hypoglycaemic and hypolipidaemic activities.
It has now surprisingly been discovered that certain novel substituted-thiazolidinedione derivatives show improved blood-glucose lowering activity and are therefore of potential use in the treatment and/or prophylaxis of hyperglycaemia and are of particular use in the treatment of Type II diabetes. These compounds are also indicated to be of potential use for the treatment and/or prophylaxis of other diseases including hyperlipidaemia and hypertension.
They are also indicated to be of use in the treatment and/or prophylaxis of cardiovascular disease, especially atherosclerosis. In addition these compounds are considered to be useful for treating certain eating disorders, in particular the regulation of appetite and food intake in subjects suffering from disorders associated with under-eating, such as anorexia nervosa, and disorders associated with over-eating, such as obesity and anorexia bulimia.
Accordingly, the present invention provides a compound of formula (I): 
or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, wherein:
A1 represents a substituted or unsubstituted aromatic heterocyclyl group;
R1 represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group;
R2 and R3 each represent hydrogen, or R2 and R3 together represent a bond;
A2 represents a benzene ring having in total up to five substituents; and
n represents an integer in the range of from 2 to 6.
Suitable aromatic heterocyclyl groups include substituted or unsubstituted, single or fused ring aromatic heterocyclyl groups comprising up to 4 hetero atoms in each ring selected from oxygen, sulphur or nitrogen.
Favoured aromatic heterocyclyl groups include substituted or unsubstituted single ring aromatic heterocyclyl groups having 4 to 7 ring atoms, preferably 5 or 6 ring atoms.
In particular, the aromatic heterocyclyl group comprises 1, 2 or 3 heteroatoms, especially 1 or 2, selected from oxygen, sulphur or nitrogen.
Suitable values for A1 when it represents a 5-membered aromatic heterocyclyl group include thiazolyl and oxazolyl, especially oxazolyl.
Suitable values for A1 when it represents a 6-membered aromatic heterocyclyl group include pyridyl or pyrimidinyl.
Suitably R2 and R3 each represent hydrogen.
Preferably, A1 represents a moiety of formula (a), (b) or (c): 
wherein:
R4 and R5 each independently represents a hydrogen atom, an alkyl group or a substituted or unsubstituted aryl group or when R4 and R5 are each attached to adjacent carbon atoms, then R4 and R5 together with the carbon atoms to which they are attached form a benzene ring wherein each carbon atom represented by R4 and R5 together may be substituted or unsubstituted; and in the moiety of formula (a)
X represents oxygen or sulphur.
Aptly, A1 represents a moiety of the abovedefined formula (a).
Aptly, A1 represents a moiety of the abovedefined formula (b).
Aptly, A1 represents a moiety of the abovedefined formula (c).
In one favoured aspect R4 and R5 together represent a moiety of formula (d): 
wherein R6 and R7 each independently represent hydrogen, halogen, substituted or unsubstituted alkyl or alkoxy.
Suitably, R6 and R7 each independently represent hydrogen, halogen, alkyl or alkoxy.
Favourably, R6 represents hydrogen. Favourably, R7 represents hydrogen.
Preferably, R6 and R7 both represent hydrogen.
In a further favoured aspect R4 and R5 each independently represent hydrogen, alkyl or a substituted or unsubstituted phenyl group and more favourably, R4 and R5 each independently represent hydrogen, alkyl or phenyl.
Preferably, for the moiety of formula (a), R4 and R5 together represent the moiety of formula (d).
Preferably, for the moieties of formula (b) or (c), R4 and R5 both represent hydrogen.
It will be appreciated that the five substituents of A2 include three optional substituents. Suitable optional substituents for the moiety A2 include halogen, substituted or unsubstituted alkyl or alkoxy.
Favourably, A2 represents a moiety of formula (e): 
wherein R8 and R9 each independently represent hydrogen, halogen, substituted or unsubstituted alkyl or alkoxy.
Suitably, R8 and R9 each independently represent hydrogen, halogen, alkyl or alkoxy. Preferably, R8 and R9 each represent hydrogen.
Favourably, X represents oxygen. Favourably, x represents sulphur.
In one preferred aspect the present invention provides a class of compounds, which fall wholly within the scope of formula (I), of formula (II): 
or a tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, wherein A1, R1, R2, R3, and n are as defined in relation to formula (I) and R8 and R9 are as defined in relation to formula (e).
Suitably, n represents an integer 2, 3 or 4, notably 2 or 3 and especially 2.
Suitably, R1 represents hydrogen, alkyl, acyl, especially acetyl, or benzyl.
When R1 represents an alkyl group, examples of such alkyl groups include methyl and isopropyl. Preferably, R1 represents a methyl group.
As indicated above a compound of formula (I) may exist in one of several tautomeric forms, all of which are encompassed by the present invention. It will be appreciated that the present invention encompasses all of the isomeric forms of the compounds of formula (I) and the pharmaceutically acceptable salts thereof, including any stereoisomeric forms thereof, whether as individual isomers or as mixtures of isomers.
Suitable substituents for any heterocyclyl group include up to 4 substituents selected from the group consisting of: alkyl, alkoxy, aryl and halogen or any two substituents on adjacent carbon atoms, together with the carbon atoms to which they are attached, may form an aryl group, preferably a benzene ring, and wherein the carbon atoms of the aryl group represented by the said two substituents may themselves be substituted or unsubstituted.
When used herein the term xe2x80x98arylxe2x80x99 includes phenyl and naphthyl optionally substituted with up to five, preferably up to three, groups selected from halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxy, amino, nitro, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, or alkylcarbonyl groups.
When used herein the term xe2x80x98halogenxe2x80x99 refers to fluorine, chlorine, bromine and iodine; preferably chlorine.
When used herein the terms xe2x80x98alkylxe2x80x99 and xe2x80x98alkoxyxe2x80x99 relate to groups having straight or branched carbon chains,containing up to 12 carbon atoms.
When used herein the term xe2x80x98acylxe2x80x99 includes alkylcarbonyl groups.
Suitable alkyl groups are C1-12 alkyl groups, especially C1-6 alkyl groups e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl or tert-butyl groups.
Suitable substituents for any alkyl group include those indicated above in relation to the term xe2x80x9carylxe2x80x9d.
Suitable pharmaceutically acceptable salts include salts of the thiazolidinedione moiety, and, where appropriate, salts of carboxy groups.
Suitable pharmaceutically acceptable salts of the thiazolidinedione moiety include metal salts especially alkali metal salts such as the lithium, sodium and potassium salts.
Suitable pharmaceutically acceptable salts of carboxy groups include metal salts, such as for example aluminium, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl-xcex2-phenethylamine, dehydroabietylamine, N,Nxe2x80x2-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine or quinoline.
Suitable pharmaceutically acceptable solvates include hydrates.
In a further aspect the present invention also provides a process for the preparation of a compound of formula (I), or a tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, which process comprises reacting a compound of formula (III): 
wherein R2, R3 and A2 are as defined in relation to formula (I), and Ra is a moiety convertible to a moiety of formula (f): 
wherein R1, A1, and n are as defined in relation to formula (I), with an appropriate reagent capable of converting Ra to the said moiety (f) and thereafter, if required, carrying out one or more of the following optional steps:
(i) converting a compound of formula (I) to a further compound of formula (I);
(ii) preparing a pharmaceutically acceptable salt of the compound of formula (I) and/or a pharmaceutically acceptable solvate thereof.
Suitably, Ra represents R1HNxe2x80x94(CH2)nxe2x80x94Oxe2x80x94 wherein R1 and n are as defined in relation to formula (I).
Suitably, when Ra is R1HNxe2x80x94(CH2)nxe2x80x94Oxe2x80x94, an appropriate reagent capable of converting Ra to a moiety (f) is a compound of formula (IV):
A1xe2x80x94RXxe2x80x83xe2x80x83(IV)
wherein A1 is as defined in relation to formula (I) and Rx represents a leaving group.
A suitable leaving group Rx includes a halogen atom, preferably a chlorine or bromine atom, or a thioalkyl group for example a thiomethyl group.
The reaction between the compound of formula (III) and the appropriate reagent may be carried out under conditions suitable to the particular compound of formula (III) and the reagent chosen; thus for example the abovementioned reaction between a compound of formula (III) wherein Ra represents R1HNxe2x80x94(CH2)nxe2x80x94Oxe2x80x94 and the compound of formula (IV), may be carried out in any suitable solvent, for example tetrahydrofuran, at a temperature in the range of between 0 and 60xc2x0 C.
A compound of formula (III) may be prepared from a compound of formula (V): 
wherein A2 is as defined in relation to the compound of formula (I) and Rb is a moiety Ra, or a moiety convertible to a moiety Ra; by reaction of the compound of formula (V) with 2,4-thiazolidinedione; and thereafter if required carrying out one or more of the following optional steps:
(i) reducing a compound of formula (III) wherein R2 and R3 together represent a bond, into a compound of formula (III) wherein R2 and R3 each represent hydrogen;
(ii) converting a moiety Rb to a moiety Ra.
The reaction between the compound of formula (V) and 2,4-thiazolidinedione will of course be carried out under conditions suitable to the nature of the compound of formula (V), in general the reaction being carried out in a solvent such as toluene, suitably at an elevated temperature such as the reflux temperature of the solvent and preferably in the presence of a suitable catalyst such as piperidinium acetate or benzoate. Favourably, in the reaction between the compound of formula (V) and 2,4-thiazolidinedione, the water produced in the reaction is removed from the reaction mixture, for example by means of a Dean and Stark apparatus.
When Ra represents R1HNxe2x80x94(CH2)nxe2x80x94Oxe2x80x94, a suitable value for Rb is a hydroxyl group.
The moiety Rb may be converted to the moiety Ra by any suitable means, for example when Rb represents a hydroxyl group and Ra represents R1HN(CH2)nxe2x80x94Oxe2x80x94 the appropriate conversion may be carried out by coupling a compound of formula (VA): 
wherein R2, R3 and A2 are as defined in relation to formula (I) and Rz is hydrogen or a nitrogen protecting group, with a compound of formula (VI):
R1NRx(CH2)nxe2x80x94OHxe2x80x83xe2x80x83(VI)
wherein R1 and n are as defined in relation to formula (I) and Rx is hydrogen or a nitrogen protecting group, in the presence of a suitable coupling agent; and thereafter, if required, carrying out one or more of the following optional steps:
(i) reducing a compound of formula (III) wherein R2 and R3 together represent a bond, to a compound of formula (III) wherein R2 and R3 each represent hydrogen;
(ii) removing any nitrogen protecting group.
A suitable coupling agent for the coupling reaction between the compound of formula (VA) and (VI) is provided by diethylazodicarboxylate and triphenylphosphine. The coupling reaction may be carried out in any suitable solvent at a low to medium temperature, for example in tetrahydrofuran at a temperature in the range of between 0 and 60xc2x0 C.
One example of the preparation of a compound of formula (VA) is that wherein a compound falling within formula (V) of particular formula (VII): 
wherein A2 is as defined in relation to formula (I), and R11 represents a hydroxyl group or a protected hydroxyl group, is reacted with 2,4-thiazolidinedione; and thereafter if required removing any protecting group.
Preferably, R11 represents a benzyloxy group.
Suitable conditions for the reaction between a compound of formula (VII) and 2,4-thiazolidinedione are those defined above in relation to the reaction between the compounds of formula (V) and 2,4-thiazolidinedione.
The compounds of formula (IV), (VI) and (VII) are either known compounds or are prepared using methods analogous to those used to prepare known compounds.
Suitable protecting groups in any of the abovementioned reactions are those used conventionally in the art. Thus, for example, a suitable nitrogen protecting group is a benzyl group or a benzyloxycarbonyl group and a suitable hydroxyl protecting group is a benzyl group.
The methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected. Thus for example when R11 represents a benzyloxy group such group may be prepared by treatment of the appropriate compound of formula (VII), wherein R11 is a hydroxyl group with a benzyl halide, such as benzyl bromide, and thereafter when required the benzyl group may be conveniently removed using a mild ether cleavage reagent such as trimethylsilyliodide.
A compound of formula (I), or a tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, may also be prepared by reacting a compound of formula (VIII): 
wherein R1, A1, A2, and n are as defined in relation to formula (I) with 2,4-thiazolidinedione; and thereafter if required carrying out one or more of the following optional steps:
(i) converting a compound of formula (I) into a further compound of formula (I);
(ii) preparing a pharmaceutically acceptable salt of a compound of formula (I) and/or a pharmaceutically acceptable solvate thereof.
The reaction between a compound of formula (VIII) and 2,4-thiazolidinedione may suitably be carried out under analogous conditions to those used in the reaction between a compound of formula (V) and 2,4-thiazolidinedione.
A compound of formula (VIII) may be prepared by reacting a compound of formula (IX): 
wherein A2 is as defined in relation to formula (I) and Ra is as defined in relation to formula (III), with an appropriate reagent capable of converting Ra to the above defined moiety (f).
Suitable values for Ra include those described above in relation to the compound of formula (III). Thus Ra may represent R1HNxe2x80x94(CH2)nxe2x80x94Oxe2x80x94, as defined above, and hence the appropriate compound of formula (IX) may be reacted with a reagent of the abovedefined formula (IV) to provide the required compound of formula (VIII).
Suitable reaction conditions for the reaction of the compound of formula (IX) and the appropriate reagent may include those described above in relation to the preparation of compound (III) with the said appropriate reagent.
Preferably, for the compound of formula (IX), Ra represents a leaving group, especially a fluorine atom. When Ra represents a leaving group, preferably a fluorine atom, a particularly appropriate reagent is a compound of formula (X): 
wherein R1, A1, and n are as defined in relation to formula (I).
The reaction between the compounds of formulae (IX) and (X) may be carried out under any suitable conditions, for example in a solvent such as dimethylformamide or dimethylsulphoxide at an elevated temperature for example in the range of between 100 to 150xc2x0 C., suitably in the presence of a base such as sodium hydride or potassium carbonate.
In the compound of formula (IX) Ra may also represent a hydroxyl group.
When Ra, in the compound of formula (IX), represents a hydroxyl group a particularly appropriate reagent is a compound of the abovedefined formula (X) or a compound of formula (XA): 
wherein A1, R1 and n are as defined in relation to formula (X) and Ry represents a tosylate or mesylate group.
The reaction between the compound of formula (IX) wherein Ra is a hydroxyl group and the reagent of the abovedefined formula (X) may suitably be carried out in an aprotic solvent, such as tetrahydrofuran, at low to medium temperature, for example at ambient temperature, and preferably in the presence of a coupling agent such as that provided by triphenylphosphine and diethylazodicarboxylate.
The reaction between the compound of formula (IX), wherein Ra is a hydroxyl group, and the reagent of the abovedefined formula (XA) may be carried out in an aprotic solvent, such as dimethylformamide, at a low to elevated temperature, for example in the range of from 50xc2x0 C. to 120xc2x0 C. and preferably in the presence of a base, such as sodium hydride.
The compound of formula (XA) may be prepared from the corresponding compound of formula (X) by reaction with either a tosyl halide or a mesyl halide in a solvent such as pyridine.
The compounds of formula (IX) are known compounds or compounds prepared by methods analogous to those used to prepare known compounds, for example 4-fluorobenzaldehyde and 4-hydroxybenzaldehyde are known commercially available compounds.
The reagent of formula (X) may be prepared by reacting a compound of the hereinabove defined formula (IV), with a compound of the hereinbefore defined formula (VI) and thereafter if required removing any nitrogen protecting group using the appropriate conventional conditions.
The reaction between the compounds of formula (IV) and (VI) may be carried out under any suitable conditions, such as in solvent, for example in an aprotic solvent such as tetrahydrofuran, at a low to medium temperature, for example a temperature in the range of from 0 to 60xc2x0 C.
Favourably when R1 represents hydrogen the reaction is carried out using the compound of formula (VI) as a solvent at a low to elevated temperature, suitably an elevated temperature such as in the range of between 100 and 170xc2x0 C.
The abovementioned conversion of a compound of formula (I) into a further compound of formula (I) includes the following conversions:
(a) reducing a compound of formula (I) wherein R2 and R3 together represent a bond, to a compound of formula (I) wherein R2 and R3 each represent hydrogen; and
(b) converting one group R1 into another group R1.
The conversion of a compound of formula (I) to a further compound of formula (I) may be carried out by using any appropriate conventional procedure.
A suitable reduction method for the abovementioned conversion (a) includes catalytic reduction or the use of a metal/solvent reducing system.
Suitable catalysts for use in the catalytic reduction are palladium on carbon catalysts, preferably a 10% palladium on charcoal catalyst; the reduction being carried out in a solvent, for example dioxan, suitably at ambient temperature.
Suitable metal/solvent reducing systems include magnesium in methanol.
The abovementioned reduction of a compound of formula (III) wherein R2 and R3 together represent a bond to a compound of formula (III) wherein R2 and R3 each represent hydrogen, may be carried out under analogous conditions to those referred to above in conversion (a) of the compound of formula (I).
In the abovementioned conversion (b), suitable conversions of one group R1 into another group R1 includes converting a group R1 which represents hydrogen into a group R1 which represents an acyl group.
The conversion of a compound of formula (I) wherein R1 represents hydrogen into a compound of formula (I) wherein R1 represents acyl may be carried out using any appropriate conventional acylation procedure, such as by treating an appropriately protected compound of formula (I) with an acylating agent. For example acetic anhydride may be used to prepare the compound of formula (I) wherein R1 is acetyl.
It will be appreciated that in the abovementioned conversions (a) and (b), any reactive group in the compound of formula (I) would be protected, according to conventional chemical practice, where necessary.
Where appropriate the isomeric forms of the compounds of formula (I) and the pharmaceutically acceptable salts thereof may be prepared as individual isomers using conventional chemical procedures.
As mentioned above the compounds of the invention are indicated as having useful therapeutic properties:
The present invention accordingly provides a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance.
Thus the present invention provides a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use in the treatment of and/or prophylaxis of hyperglycaemia, hyperlipidaemia and hypertension.
A compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, maybe administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.
Accordingly, the present invention also provides a pharmaceutical composition comprising a compound of the general formula (I), or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier therefor.
As used herein the term xe2x80x98pharmaceutically acceptablexe2x80x99 embraces compounds, compositions and ingredients for both human and veterinary use: for example the term xe2x80x98pharmaceutically acceptable saltxe2x80x99 embraces a veterinarily acceptable salt.
The composition may, if desired, be in the form of a pack accompanied by written or printed instructions for use.
Usually the pharmaceutical compositions of the present invention will be adapted for oral administration, although compositions for administration by other routes, such as by injection and percutaneous absorption are also envisaged.
Particularly suitable compositions for oral administration are unit dosage forms such as tablets and capsules. Other fixed unit dosage forms, such as powders presented in sachets, may also be used.
In accordance with conventional pharmaceutical practice the carrier may comprise a diluent, filler, disintegrant, wetting agent, lubricant, colourant, flavourant or other conventional adjuvant.
Typical carriers include, for example, microcrystalline cellulose, starch, sodium starch glycollate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, magnesium stearate, sodium lauryl sulphate or sucrose.
Most suitably the composition will be formulated in unit dose form. Such unit dose will normally contain an amount of the active ingredient in the range of from 0.1 to 1000 mg, more usually 0.1 to 500 mg, and more especially 0.1 to 250 mg.
The present invention further provides a method for the treatment and/or prophylaxis of hyperglycaemia or hyperlipidaemia in a human or non-human mammal which comprises administering an effective, non-toxic, amount of a compound of the general formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof to a hyperglycaemic human or non-human mammal in need thereof.
The present invention further provides a method or he treatment of cardiovascular disease, especially atherosclerosis, in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, to a human or non-human mammal in need thereof.
The present invention also provides a method for the treatment of certain eating disorders, in particular the regulation of appetite and food intake in disorders associated with under-eating, such as anorexia nervosa, and disorders associated with over-eating, such as obesity and anorexia bulimia, in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, to a human or non-human mammal in need thereof.
Conveniently, the active ingredient may be administered as a pharmaceutical composition hereinbefore defined, and this forms a particular aspect of the present invention.
In the above mentioned treatments the compound of the general formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, may be taken in doses, such as those described above, one to six times a day in a manner such that the total daily dose for a 70 kg adult will generally be in the range of from 0.1 to 6000 mg, and more usually about 1 to 1500 mg.
In the treatment and/or prophylaxis of hyperglycaemic non-human mammals, especially dogs, the active ingredient may be adminstered by mouth, usually once or twice a day and in an amount in the range of from about 0.025 mg/kg to 25 mg/kg, for example 0.1 mg/kg to 20 mg/kg. Similar dosage regimens are suitable for the treatment and/or prophylaxis of hyperlipidaemia in non-human mammals.